Serum 25(OH)D is prevalently low in older people and more than 60% North American female populations are below the optimal level. Low serum 25(OH)D is a serious problem since optimal serum 25(OH)D concentration is essential for preventing cancer and other disorders. Currently, vitamin D supplementation is the best approach in achieving adequate serum 25(OH)D levels. However, the change in serum 25(OH)D in response to a given dose of vitamin D supplementation varies widely from person to person and the factors underlying the variability are unknown. The unknown factors are likely genetic because both baseline serum 25(OH)D and the response to vitamin D intake are highly genetically determined. Currently, few genetic studies are available in this area. The specific genes underlying the response variability in serum 25(OH)D in different individual are unknown. By taking advantage of the large-size, homogeneous, unique, longitudinal, population-based, and high-dose vitamin D intervention trial sample from the parent study (R01CA129488), the primary objective of the revision is to identify genetic variants responsible for the variability in serum 25(OH)D levels. The central hypothesis is that genes functionally important for vitamin D metabolism and signaling pathways are involved in the variation of serum 25(OH)D levels in postmenopausal women. To test this hypothesis, eight prominent candidate genes have been selected. The specific aims are to: 1) identify the genetic variants responsible for the baseline serum 25(OH)D variation;2) identify the genetic variants responsible for the response variability in serum 25(OH)D levels. For specific aim 1, the sample will be the entire cohort (n=2300) of non-Hispanic, white postmenopausal women. The targeted phenotype is baseline serum 25(OH)D variation. For specific aim 2, only subjects in the calcium (1200 mg/d) and vitamin D (2000 IU/d) intervention group (n=1150) will be used. The phenotype (endpoint) is the change of 12-month serum 25(OH)D in response to vitamin D supplementation. This revision proposal is highly innovative. It will yield additional critical information and will add value to the parent study. It is the first attempt to identify genetic factors responsible for variability in serum 25(OH)D in response to vitamin D supplementation. In addition, for the first time, it will address whether genes responsible for baseline serum 25(OH)D variation also account for the response variability in serum 25(OH)D. The genetic factors identified from this revision are important for understanding the mechanisms accounting for population variation in prevalent vitamin D status, and for individualizing dosing with vitamin D supplementation.